Solid organ transplantation is currently the treatment of choice for children with a variety of end-stage organ diseases. The success of clinical transplantation is dependent on the use of potent immunosuppressive drugs to prevent rejection of the allograft. However, chronic immunosuppression is linked to a number of serious side effects in children including an increased risk of infection and de novo malignancies. Post-transplant lymphoproliferative disorder (PTLD) is the most common malignancy in this population, occurring in 10% of pediatric heart, 1-3% of kidney, 1-3% of liver, and 10-30% of small bowel transplant recipients. PTLD describes a spectrum of abnormal B cell lymphoproliferations associated with Epstein-Barr Virus (EBV) infection, the most serious of which manifest as frank lymphoma. As the risk of developing PTLD is greater in patients who are EBV seronegative at the time of transplant, infants and children are at particular risk. Currently, there is no EBV vaccine available; reduction in immunosuppression and antiviral therapy are used as the first line of treatment. However, there are major gaps in our understanding of the immune response to EBV infection in the immunosuppressed patient and no clear evidence that current therapies are effective. Advances in this field are limited by the absence of proven biomarkers to reliably diagnose EBV-associated cancers and to follow those who are at highest risk. We hypothesize that unique molecular and functional changes in the EBV genome, the infected B cells, and the responsive T cells occur in transplant recipient children with EBV disease and that these changes can be utilized as novel biomarkers associated with detection and prognosis of EBV-positive PTLD. We have developed compelling preliminary data suggesting that the attainment of such biomarkers may be within reach. In this observational study, coupled with a strong mechanistic component, we bring together 5 leading pediatric programs in heart, liver and small intestinal transplantation to identify biomarkers of EBV disease and its progression to PTLD. To test this hypothesis we propose the following specific aims: Aim 1: Assess gain of function mutations in the EBV protein LMP1 as a biomarker for PTLD risk. Aim 2: Assess the emergence of pathogenic B cell clonotypes using high-throughput V(D)J sequencing as a biomarker for emergence of pre-clinical PTLD. Our goal is the development of a biomarker that would identify patients at risk for PTLD or those in the very early stages of the disease, which will represent a major advance in pediatric solid organ transplantation.